INTRODUCTION
Giant cell arteritis (GCA) is the most common vasculitis in western countries3. It usually involves large and medium-sized blood vessels with predisposition to the cranial arteries3,17. Its frequency increases with age and peaks in those groups of patients older than 70 years10.
Classically, patients with GCA present with clinical manifestations that are the result of vascular involvement. Since healed arteritis is often difficult to differentiate from arteriosclerosis on morphologic grounds, some investigators have suggested that arteriosclerosis and GCA may have a common pathway15,16. Machado et al12, in a retrospective case-control study of 88 patients with biopsy-proven GCA, reported an association between smoking and disease development in 1989. In 1998, Duhaut et al1, in a prospective multicenter case-control study of 207 patients with biopsy-proven GCA, described a strong association between smoking and previous atheromatous disease in women and GCA.
Because the prognosis of GCA is directly related to the development of ischemic complications, an important step forward in understanding this condition and its complications may be to assess the potential influence of traditional risk factors of atherosclerosis in the development of severe ischemic complications of GCA. We therefore assessed whether the presence of atherosclerosis risk factors at the time of GCA diagnosis might influence the occurrence of ischemic manifestations in a large series of patients with biopsy-proven GCA.
PATIENTS AND METHODS
We conducted a retrospective review of the case records of all patients diagnosed with biopsy-proven GCA at the Department of Medicine of the Hospital Xeral-Calde (Lugo, Spain) between January 1981 and December 2001. The characteristics of this white population of almost 250,000 people have been described previously2.
The temporal artery biopsy procedure in Lugo patients has been reported elsewhere7,8. Patients were diagnosed as having biopsy-proven GCA when the temporal artery biopsy showed a compatible pathology report describing the characteristic mononuclear cell infiltration of the arterial wall, with or without granulomas and/or multinucleated giant cells11.
Clinical Definitions
Clinical definitions of GCA manifestations in the Lugo population have also been described previously7,8. As described6, patients were considered to have severe ischemic manifestations if they suffered visual manifestations (transient visual loss including amaurosis fugax, permanent visual loss, or diplopia), cerebrovascular accidents (stroke and/or transient ischemic attacks), and jaw claudication. In addition, to encompass all of the severe ischemic complications related to GCA, we included in this category patients with large-artery stenosis of the extremities that caused signs of occlusive manifestations (limb claudication) of recent onset.
For the purpose of this study, severe ischemic complications were attributed to GCA if they occurred within the time between the onset of GCA symptoms and 4 weeks after the onset of corticosteroid therapy (initial dose 40-60 mg prednisone/day for 3-4 weeks or intravenous methylprednisolone pulse therapy [1 g daily for 3 days] followed by 60 mg prednisone/day for 3-4 weeks in most patients who had visual manifestations).
Concerning classic (traditional) risk factors of atherosclerosis: the vast majority of patients included in this study were admitted to hospital for disease diagnosis. This fact allowed us to assess in all patients smoking history, blood pressure, and cholesterol and glucose levels.
Patients were considered to have hypercholesterolemia if before the diagnosis of GCA they had been diagnosed as having hypercholesterolemia by their family physician, or if at the time of disease diagnosis the total cholesterol level in fasting plasma was greater than 260 mg/dL. Patients were considered to have hypertension if before the diagnosis of GCA they had been diagnosed as having hypertension by their family physician or if at the time of diagnosis they had a blood pressure greater than 150/90 mm Hg in 2 different determinations performed on different days. GCA patients were considered to have diabetes mellitus if before the GCA diagnosis they had been diagnosed as having diabetes mellitus by their family physician or if a plasma glucose concentration at the time of admission was greater than 140 mg/dL. To make a definitive diagnosis of diabetes mellitus in those patients not previously diagnosed as having this condition who had glycemia values greater than 140 mg/dL at the time of admission, a second determination (fasting overnight venous determination) yielding glycemia values greater than 140 mg/dL before or within 24-48 hours after the onset of corticosteroid therapy was required. With regard to smoking, we established 2 categories: heavy smokers, encompassing those patients who still smoked at the time of disease diagnosis or who had smoked within the 10 years before the onset of GCA symptoms, and the remaining patients (those who never smoked or stopped smoking at least 10 years before the disease onset).
Data Collection
We analyzed demographic and clinical data at the time of diagnosis for all patients with biopsy-proven GCA. Also, erythrocyte sedimentation rate (ESR), hemoglobin, platelet count, cholesterol, and glucose on admission were assessed.
Statistical Analysis
Comparisons between 2 categories were made using the Student t test (2-tailed) for continuous variables. To analyze categorical data, we performed a chi-square test or a Fisher exact test. The relationship between severe ischemic complications of GCA and traditional risk factors of atherosclerosis was assessed by logistic regression analysis. In all cases, odds ratios (OR) and their 95% confidence intervals (CI) were assessed. Statistical significance was defined as p ≤ 0.05. Calculations were performed with the statistical package Stata 8/SE (Stata Corporation, College Station, TX).
RESULTS
Between January 1981 and December 2001, 210 consecutive patients were diagnosed with biopsy-proven GCA. All of them fulfilled the 1990 American College of Rheumatology criteria for the classification of GCA9. At the time of GCA diagnosis, 116 (55.2%) had at least 1 of the atherosclerosis risk factors assessed in this study.
Severe Ischemic Manifestations in 210 Patients With Biopsy-Proven GCA
Since the purpose of the present study was to assess the influence of traditional risk factors of atherosclerosis in the spectrum of clinical manifestations of GCA, we examined those severe ischemic manifestations that occurred from the onset of symptoms of the disease until 1 month after adequate therapy (at least 40 mg prednisone/day) had been started (Table 1).
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TABLE 1: Main Ischemic Complications Observed Between the Onset of Symptoms of GCA and 1 Month After the Onset of Steroid Therapy
Jaw claudication was the most common severe ischemic complication (41%). In all cases it was present at the time of disease diagnosis. Permanent visual loss was found in 27 patients (12.9%). It was preceded by amaurosis fugax in 12 (44.4%) of the 27 cases. However, none of the patients without ocular manifestations before treatment and who received adequate treatment for at least 3 days developed visual impairment.
Three patients (1.4%) had a vertebro-basilar stroke, 3.5, 7, and 10 days after the onset of steroid therapy, respectively. Another suffered 2 episodes consistent with transient ischemic attacks within the month before GCA diagnosis and also had a cerebrovascular stroke in the carotid territory at the time of admission. As described before5,14, 6 (2.9%) patients had limb claudication due to ischemia involving arteries of the upper extremities in 2 patients (axillary and humeral) and the lower extremities in 4 (3 aortoiliac and 1 femoral arterial stenosis) that occurred between the onset of GCA manifestations and diagnosis.
Complete evidence for causality between ischemic events and disease in this series of patients with biopsy-proven GCA and in former studies of this vasculitis is absent. However, in all cases described in the current study, ischemic events occurred associated with other classical clinical features of the disease or with abnormality of laboratory data (high ESR in all cases). Thus, we may assume that the ischemic events were probably due to or promoted by the vasculitis. In addition, only 1 of the 12 GCA patients found to have atrial fibrillation at the time of GCA diagnosis suffered visual manifestations (anterior ischemic optic neuritis). None of these 12 patients with atrial fibrillation had central retinal artery occlusion, cerebrovascular accidents, or claudication of the extremities.
Differences Between Patients With and Without Traditional Atherosclerosis Risk Factors
No differences according to sex, age at the time of diagnosis of GCA, or delay to the diagnosis were found between GCA patients with and without atherosclerosis risk factors (Table 2). Jaw claudication and visual ischemic manifestations were more commonly observed in patients with atherosclerosis risk factors than in those without; however, the difference was not statistically significant. In contrast, patients with traditional atherosclerosis risk factors had fever (temperature at admission or during follow-up before the onset of corticosteroid therapy ≥38°C, confirmed by a health care professional)6 less commonly than those without classic atherosclerosis risk factors (5.2% vs. 16.0%; p = 0.01). Finally, no differences in the laboratory markers of inflammatory response were observed (see Table 2).
TABLE 2: Clinical and Laboratory Features in Biopsy-Proven GCA Patients With and Without Traditional Atherosclerosis Risk Factors (Hypercholesterolemia, Diabetes Mellitus, Hypertension, or Heavy Smoking)
Relationship Between the Traditional Risk Factors of Atherosclerosis and the Development of Severe Ischemic Complications of GCA
When we assessed patients with biopsy-proven GCA for the risk of severe ischemic complications, we found that the presence of traditional risk factors of atherosclerosis before the diagnosis of the vasculitis significantly increased the risk of developing at least 1 of the severe ischemic complications described above (OR, 1.79; 95% CI, 1.03-3.11; p = 0.04) (Table 3).
TABLE 3: Relationship Between the Traditional Risk Factors of Atherosclerosis (Hypercholesterolemia, Diabetes Mellitus, Hypertension, or Heavy Smoking) and the Development of Severe Ischemic Complications in GCA
Traditional Risk Factors of Atherosclerosis in Biopsy-Proven GCA: Differences Between Patients With and Without Severe Ischemic Manifestations
Only biopsy-proven GCA patients with hypertension exhibited a significantly increased risk of developing severe ischemic complications (OR, 1.80; 95% CI, 1.00-3.25; p = 0.05) (Table 4).
TABLE 4: Traditional Risk Factors of Atherosclerosis in Biopsy-Proven GCA: Differences Between Patients With and Without Severe Ischemic Manifestations (Visual Complications, Jaw Claudication, Cerebrovascular Manifestations, or Limb Claudication of Recent Onset)
Impact of Antiaggregation or Anticoagulation on the Risk of Severe Ischemic Complications
Fourteen patients were on antiaggregation therapy (11 received aspirin 100-250 mg/day and 3 received triflusal 300 mg/day) and 1 was under acenocoumarol treatment before the onset of GCA manifestations. However, no statistically significant reduction in the incidence of severe ischemic manifestations was observed in this group of patients compared with the remaining patients (Table 5).
TABLE 5: Impact of Antiaggregation or Anticoagulation Before the Onset of GCA Symptoms on the Development of Severe Ischemic Manifestations
DISCUSSION
Fifteen years ago Machado et al12 suggested that GCA and arteriosclerosis might share a common causal pathway. These authors found an increased risk, which was not statistically significant, for angina, myocardial infarction, and peripheral vascular disease in a series of 88 patients with GCA. They also observed a significantly increased risk of GCA among smokers from Olmsted County, MN12. Heavy smoking and previous atheromatous disease was associated with an increased risk of GCA in French women1.
Some differences among the studies by Machado et al12 and Duhaut et al1 and the current study exist. We have not intended to examine the potential association between a previous history of arteriosclerosis and the occurrence of GCA, but to investigate specifically the potential influence of traditional risk factors of atherosclerosis on the development of severe ischemic manifestations of GCA. The current study suggests that the presence of atherosclerosis risk factors at the time of GCA diagnosis may influence the development of severe ischemic complications in patients with this vasculitis.
Patients with traditional atherosclerosis risk factors had an increased risk of developing at least 1 severe ischemic manifestation, and fever at the time of diagnosis was found less commonly in these patients than in those without the traditional risk factors. In this regard, we have observed recently that in our population, the group of GCA patients with fever had less frequency of severe ischemic manifestations than the rest of the patients6. By logistic regression analysis we observed a negative association between severe ischemic manifestations at the time of diagnosis of the disease and fever (OR, 0.41) in GCA patients from Lugo6. Also, patients with fever exhibited a more severe inflammatory disease, with significant abnormality in most laboratory parameters of inflammation6. However, why GCA patients with traditional atherosclerosis risk factors have a lower frequency of fever remains an intriguing question. It is possible that, due to severe and maintained inflammatory response, fever might represent the clinical expression of an angiogenic activity, which might play a compensatory role for ischemia in patients with GCA. According to that, GCA patients with atherosclerosis would be unable to establish appropriate angiogenic compensatory mechanisms and, due to this, they might suffer more vascular ischemic complications.
The present study has several limitations due to its retrospective nature. Certainly, there are limitations in the definitions of hypertension and hypercholesterolemia. Defining hypercholesterolemia is difficult because standards need to be established for the population of Lugo. Also, the normal cut-off limit of cholesterol has changed over the 21 years of the study. In addition, most patients diagnosed before 1996 were not assessed for LDL or HDL cholesterol at the time of GCA diagnosis. Due to this, in this series of individuals with a mean age of 75 years at the time of GCA diagnosis, we considered hypercholesterolemia whenever the plasma cholesterol level exceeded 260 mg/dL. However, when we recalculated our study using a cut-off value of 240 mg/dL for hypercholesterolemia and 140/90 for hypertension, the results were essentially the same.
In 2002 Uddhammar et al18 reported an increased mortality due to cardiovascular disease in patients with GCA from northern Sweden. In contrast, 5 years before, we described that the long-term mortality in GCA patients from Lugo was low4. At that time we examined all follow-up information for 109 patients with biopsy-proven GCA diagnosed between January 1982 and March 1996. As observed in the elder population of Lugo, cardiovascular and cerebrovascular complications accounted for most causes of death in our series. However, the long-term mortality of GCA in the Lugo region was similar to the rate of mortality observed in the general population of the same age of this region. Similar data on low mortality related to GCA were reported by other investigators, such as Matteson et al13. These observations suggest that the traditional atherosclerosis risk factors may not play a key role for GCA incidence and mortality in all populations. Alternatively, it is possible that in some populations like ours, GCA patients might constitute a relatively "healthy" group of individuals with a minor incidence of traditional risk factors of atherosclerosis. This might explain the relatively low incidence of diabetes mellitus in our series of GCA patients. Also, although the inflammatory process by itself may affect cholesterol levels at the time of diagnosis, we were surprised to see a low incidence of previous history of hypercholesterolemia at the time of admission in our patients.
The presence of underlying atherosclerosis may have special importance, however, in the development of vascular ischemic complications of GCA. In this regard, the presence of traditional risk factors of atherosclerosis, in particular the presence of hypertension, increased the risk of severe ischemic complications in our series of patients with biopsy-proven GCA.
Our results suggest that patients with GCA should be monitored for traditional risk factors of atherosclerosis, since the presence of these factors at the time of GCA diagnosis may influence the development of severe ischemic complications. However, multicenter collaborative studies should be performed to explore further the influence of atherosclerosis in the clinical spectrum of GCA.
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